Anxiety disorders are highly prevalent in the population and carry a significant burden of distress and impairment. Only a moderate proportion of patients with anxiety disorders respond adequately to current treatments, and anxiety disorders are relatively understudied compared to other psychiatric syndromes. Exploring their genetic determinants will help elucidate their causes and guide research for prevention and new treatments. Research has documented roles for both genetic factors, likely shared with depressive disorders and anxious temperament, and exposure to environmental stressors in the development of anxiety disorders. Yet most molecular genetic studies have not taken these factors into account in their analyses. In this project, we will carefully select 10-15 candidate anxiety disorder susceptibility genes from genome-wide association analyses weighted by evidence from other human and rodent genetic studies. We will test the main and interactive effects of these genes and environmental risk factors such as childhood adversity and stressful life events for their role in anxiety spectrum phenotypes in several large, independent samples of subjects. PUBLIC HEALTH RELEVANCE: The anxiety disorders are quite common, chronic, and disabling. Many patients with these conditions either poorly tolerate or do not adequately respond to standard treatments. Both genetic factors and exposure to environmental stress contribute to their development. The identification of the genes that play a role in their susceptibility will provide new clues to their causes and, hopefully, new directions for prevention and treatment research.